The 1992 cancer statistics estimated that 181,000 new cases of invasive breast would be diagnosed that year and result in 46,300 new deaths. See Boring, C. C. et al.; Cancer, 42:19 (1992). In North America, breast cancer is the most common malignancy of women and accounts for 27% of all female cancers and 18% of all female cancer mortalities. For women aged 40-55, breast cancer represent the leading cause of death overall. While the age standardized incidence of breast cancer has risen annually (1-4% per year), the age adjusted mortality has remained stable for the past fifty years (in the U.S.A.). Most women that die from breast cancer succumb not to the original primary disease, which is usually amenable to various therapies, but rather from metastatic spread of the breast cancer to distant sites. This fact underscores the need to develop either novel anticancer agents or more aggressive forms of therapy directed specifically against the metastatic breast tumor cell. Requisite to the development of new treatment modalities is a fundamental, thorough understanding of the regulatory processes inherent to the growth of both the primary and metastatic breast cancer cell and tumor. This process has been severely hampered by the lack of appropriate and clinically relevant modeling systems. The model described here can be useful in providing the latter.
Anticancer drug screening trials have been conducted for many years using a wide variety of tumor cell lines as targets. Drugs that show anticancer activity in vitro are subsequently tested against an in vivo tumor model. While there are, in all, a large number of human tumor cell lines, the availability of human breast cancer cell lines is limited. Of the few human breast tumor cell lines that are even capable of producing a tumor in immune suppressed animals, fewer still are capable of producing a metastasizing tumor in the animal except under extreme forms of manipulation. Cell lines like MDA-MB-231 and MDA-MB-435, see Price, J. E. et al.; Cancer Res., 50:717-721 (1990), produce consistently metastasizing tumors when the cells are injected directly into the mammary fat pad of animals, such as athymic mice. On the other hand, subcutaneous injection of these cells produce tumors that are less consistently metastatic and have a different metastatic pattern than tumors implanted directly to the mammary fat pad. What is needed are cells that can produce a metastasizing tumor without the need for surgical or experimental manipulations. The invention (GI-101A) described here, as well as the xenograft line from which it was derived, consistently produce tumors and lung metastases from subcutaneous implants, thus requiring no additional experimental manipulations.
The Goodwin Institute for Cancer Research has previously developed and reported a spontaneously metastasizing human breast tumor xenograft model (GI-101). See Hurst, J. et al.; Cancer, 68:274-276 (1993). This solid tumor model, maintained through serial animal transplantation, has been described in detail. In brief, the tumor presents as a poorly differentiated mammary carcinoma with occasional acinar and ductal formation. The tumor xenograft when implanted subcutaneously grows slowly and eventually metastasizes to the lungs, lymph nodes and bone marrow of athymic murine recipients. This invention is the development of a cell line (GI-101A) from the GI-101 xenograft that is suitable for both in vitro and in vivo investigations.